Traumatic brain injury (TBI) constitutes a major worldwide public health problem with a great socio-economic impact on our society and is a leading cause of long-term disability. TBI initiates complex pathophysiological events, secondary to the immediate injury, which have been shown to enhance susceptibility to subsequent age-related neurodegenerative disease, such as Alzheimer's disease (AD). The exact mechanism of this enhanced susceptibility to AD following TBI is not known. However, clinical data from AD and human head injury patients suggest that excessive proinflammatory responses from activated microglia contribute to the pathogenesis of both disorders and could potentially be the driving force that links these two conditions. Further, there exists strong clinical and basic sciences evidence to suggest that even a single TBI can induce chronic inflammatory signaling in the brain for months to years after the initial insult. This chronic enhanced neuroinflammatory response can increase damage from future stressors placed on the brain and contribute to the development of neurodegenerative disease. This proposal will test the hypothesis that it is this chronically enhanced neuroinflammatory response that leads to the enhanced susceptibility and poorer AD-related outcomes clinically observed for TBI patients. In aim 1, we will test whether acute treatment targeting this neuroinflammatory response can protect against the neuropathology and behavioral impairments following TBI in an APP/PS1 knock-in mouse model of AD (preventing the chronically heightened inflammatory response from developing). This aim is designed to model the clinical scenario of an individual who receives acute treatment following a TBI. However, clinically many TBIs are never reported and fail to receive acute treatment. Aim 2 is designed to model the clinical scenario where an initial TBI is untreated, and to answer the question of whether these patients could still potentially benefit from late onset treatment aimed at correcting the chronically heightened inflammatory response that exists after TBI. Successful completion of this project will provide insight into the link between TBI and the subsequent development of future neurodegenerative complications. Further, successful completion of this project has important clinical implications by demonstrating a potential novel therapy for an important clinical need that has no currently available treatment. A Career Development Plan has been formalized, and includes specialty workshop participation, regular presentations of proposed research plans and results at the laboratory and research group level, presentation of independent research results in seminar format, participation in national and international scientific meetings, preparation of research proposals and publications, and development of additional career enhancing skills. An experienced mentor, a rich scientific environment, and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth, career enhancement and development into an independent academic investigator.